Vav1 degradation agent

Abstract

The application discloses a VAV1 degrading agent shown in general formula (I-1) or formula (I-2), a pharmaceutical composition, a preparation method and application of the VAV1 degrading agent in preparation of a medicine for preventing and / or treating an autoimmune disease and an inflammation indication. The compound provided by the application has good VAV1 degrading activity, can enhance the degradation of VAV1 protein by strengthening the interaction between VAV1 protein and E3 ligase, and can be used for treating and / or preventing various diseases related to VAV1, in particular, autoimmune diseases and tumors.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry and relates to a VAV1 degrading agent, particularly to a drug that can degrade VAV1, its pharmaceutical composition, preparation method, and its use in the preparation, prevention, and / or treatment of autoimmune diseases and inflammatory indications. Background Technology

[0002] Molecular gluten is a small molecule compound that can co-bind at protein-protein interaction (PPI) interfaces, primarily regulating protein function and metabolism by inducing or stabilizing PPIs. Molecular gluten degraders (MGDs) are a type of MG that bind to E3 ubiquitin ligases. The E3 ligase transfers ubiquitin to the substrate protein, marking the target protein with a degradation signal. MGDs lead to E3 ubiquitination of the target protein, which in turn leads to recognition and degradation by the proteasome. Molecular gluten has been developed to treat various diseases, such as lenalidomide drugs, which are molecular gluten compounds of the E3 ligase cereblon, and have been approved by the FDA for the treatment of hematologic malignancies such as multiple myeloma and myelodysplastic syndromes. Molecular gluten has significant application potential for drugglycated targets. VAV1, as described in this patent, has long been considered an "undrugable target." Directly targeting the GEF domain of VAV1 is challenging because inhibiting GEF activity (catalytic activity) would still preserve its scaffold protein function, leading to insufficient inhibition of VAV1 activity and severely impacting treatment efficacy. Molecular glue degraders targeting VAV1 may bring a breakthrough in the treatment of VAV1-mediated diseases.

[0003] VAV1 (Vav guanine nucleotide exchange factor 1) is a member of the guanine nucleotide exchange factor (GEF) family and is also an adaptor protein. In vertebrates, the VAV family consists of three members—VAV1, VAV2, and VAV3. VAV1 is highly specific for expression on hematopoietic cells, including T cells, B cells, dendritic cells, natural killer cells, and granulocytes, while VAV2 and VAV3 are expressed more universally.

[0004] Studies have found that VAV1 primarily regulates T cell and B cell receptor signaling, T cell activation, T helper cell differentiation, cytokine production, actin polymerization, and cytoskeleton remodeling through both GEF-dependent and GEF-independent pathways. VAV1's GEF-dependent function refers to its catalytic activity; VAV1 activates Rac / Rho family GTPases, leading to actin polymerization, integrin adhesion activation, immune synapse formation between T cells and APCs, and chemokine-mediated cell migration. VAV1's guanine nucleotide (GDP / GTP) exchange factor (GEF)-independent function refers to its "scaffolding" function. This function appears to depend on its involvement in the antigen receptor-neighbor signaling complex rather than its GEF catalytic activity. It mediates signal transduction through the binding of its adaptor domain to other proteins. Studies have shown that in GEF-inactivated mice, it exhibits normal TCR-mediated calcium release and NFAT pathway activation. VAV1 plays a crucial role in T cell development due to its involvement in the regulation and transduction of multiple signaling pathways. VAV1 deficiency leads to severe T cell developmental defects. VAV1 also has an important impact on receptor signal transduction in T / B cells and is a positive regulator of T / B cell receptor signal transduction. It also affects the migration of hematopoietic lineage cells.

[0005] Multiple studies have shown that VAV1 may be associated with autoimmune diseases and inflammation. In diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), inflammatory bowel disease (IBD), and multiple sclerosis (MS), VAV1 has been found to be closely related to the abnormal activation of T cells and B cells. Data indicate that the absence / inhibition of VAV1 can modulate autoimmunity and inflammation. Inhibition of VAV1 has also shown good pharmacodynamic responses in animals with T / B cell-mediated arthritis and colitis, supporting VAV1 as a potential therapeutic target for autoimmune diseases and inflammation. Summary of the Invention

[0006] In order to overcome the shortcomings of the prior art, the present invention aims to provide a VAV1 degrading agent, its pharmaceutical composition, preparation method and its use in the preparation, prevention and / or treatment of autoimmune diseases and inflammatory indications.

[0007] In one aspect, the present invention provides a compound of formula (I-1) or formula (I-2):

[0008]

[0009] Or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts, wherein:

[0010] R2 R 2 Each is independently selected from H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl;

[0011] R 3 Selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0012] R 4 R 5 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0013] Y 1 For N or CR c ;

[0014] m is an integer between 0 and 3;

[0015] R 6 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl.

[0016] R c Each is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl.

[0017] R f Selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O, and S.

[0018] R g Selected from arbitrarily substituted 5-10 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S.

[0019] As a preferred option, R 3Selected from H, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C1-C3 alkyl, C1-C3 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted with 1-3 halogens, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy;

[0020] R 3 H, F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, cyclopropyl are preferred, and Cl is even more preferred.

[0021] As a preferred option, R 4 R 5 Each is independently selected from H, F, methyl, trifluoromethyl, methoxy, or trifluoromethoxy, with H being preferred.

[0022] As a preferred option, Y 1 For CR c ;

[0023] R c The components are selected from H, F, Cl, methyl, methoxy, trifluoromethyl, and trifluoromethoxy, with H being preferred.

[0024] Preferably, m is 0, 1, or 2, with 0 being the most preferred;

[0025] R 6 It is selected from H, halogen, hydroxyl, cyano, amino, nitro, methyl, trifluoromethyl, methoxy or trifluoromethoxy, with H being preferred.

[0026] As a preferred option, R 2 R 2 Each is independently selected from H, F, Cl, C1-C3 alkyl groups optionally substituted with 1-3 halogens, C1-C3 alkoxy groups optionally substituted with 1-3 halogens, 3-6 membered cycloalkyl groups or 3-6 membered heterocycloalkyl groups optionally substituted with 1-3 halogens or C1-C3 alkyl groups, preferably H, F, Cl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl.

[0027] As a preferred option, R f It is selected from C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, (C1-C3 alkylene)-(3-8 membered cycloalkyl), (C1-C3 alkylene)-(3-8 membered heterocycloalkyl), optionally substituted with 1-3 halogens, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkylene, halo-C1-C3 alkyl, halo-C1-C3 alkylene, C1-C3 alkoxy, halo-C1-C3 alkoxy;

[0028] R f Preferred compounds include C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, and methylenecyclopentyl. , , , , , , , , , Optionally substituted with 1-3 Cl, F, methyl, ethyl, =CH2, difluoromethyl, trifluoromethyl, =CF2, vinyl, ethynyl, -CH=CH2, methoxy, difluoromethoxy, or trifluoromethoxy;

[0029] R f More , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

[0030] As a preferred option, R g Selected from 5-6 membered heterocyclic aryl groups containing 1-3 heteroatoms selected from N, O, and S, optionally substituted, and optionally substituted with 1-3 R atoms. h replace;

[0031] R g Selected from , , , , , , , , , , , , , , , , , , Preferred , , , , , , , , , , , , , , , , Choose 1-3 Rs h replace;

[0032] The R h The compounds are selected from halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered cycloalkyloxy groups, and (C1-C3 alkylene)-(3-6 membered cycloalkyl groups), wherein the C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered cycloalkyloxy groups, (C1-C3 alkylene)-(3-6 membered cycloalkyl groups), and C1-C3 alkylene groups are optionally substituted with 1-3 halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, halo-C1-C3 alkyl groups, and halo-C1-C3 alkoxy groups;

[0033] The R h Preferably, Cl, F, methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, cyclopropyloxy, cyclobutyl, and methylenecyclobutyl are used, wherein the methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, cyclopropyloxy, cyclobutyl, and methylenecyclobutyl are optionally substituted by 1-3 Cl, F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, and difluoromethoxy groups.

[0034] The R h More preferably Cl, F, methyl, propyl, difluoromethyl, trifluoromethyl, Cyclopropyl, methylenecyclopropyl, , , methoxy, difluoromethoxy, trifluoromethoxy , , , , , , Cyclobutyl , .

[0035] In another aspect, the present invention also provides the following compound or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt:

[0036]

[0037]

[0038]

[0039]

[0040]

[0041]

[0042]

[0043]

[0044] .

[0045] In another aspect, the present invention also provides the following compounds:

[0046] .

[0047] Another aspect of the present invention provides a pharmaceutical composition for degrading VAV1 protein, comprising any of the compounds described above, their deuterated forms, stereoisomers or pharmaceutically acceptable salts, and pharmaceutically acceptable carriers thereof.

[0048] Preferably, the pharmaceutical composition mediates the interaction between VAV1 protein and E3 ligase, thereby increasing the degradation of VAV1 protein.

[0049] In another aspect, the present invention provides the use of any of the compounds, deuterated derivatives, stereoisomers or pharmaceutically acceptable salts thereof, or pharmaceutical compositions thereof, in the preparation of medicaments for treating and / or preventing diseases caused by or related to VAV1 polymorphism.

[0050] In another aspect, the present invention provides the use of any of the compounds, deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, or any of the pharmaceutical compositions thereof, in the preparation of a medicament for treating and / or preventing diseases caused by or related to immune abnormalities in the body.

[0051] Preferably, the disease refers to an autoimmune disease or a tumor.

[0052] Preferably, the autoimmune diseases are selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, Sjögren's syndrome, Graves' disease, type I diabetes and related diseases, vasculitis, urticaria, pulmonary hypertension, pemphigus, pernicious anemia and blood diseases mediated by autoimmune abnormalities, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata and other diseases, autoimmune nephritis, cutaneous manifestations of immune-mediated diseases, systemic sclerosis, morphine scleroderma, graft-versus-host disease, T-cell mediated nephropathy, biliary sclerosis, sclerosing cholangitis, autoimmune liver disease, chronic inflammatory demyelinating diseases, ankylosing spondylitis, axial spondyloarthritis, and alopecia areata.

[0053] The inflammatory diseases mentioned include asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, pericarditis, myocarditis, hepatitis, pulmonary fibrosis, macular degeneration, generalized undulating hematoma, Alzheimer's disease, and amyloidosis.

[0054] The allergic diseases mentioned include allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis, and esophagitis.

[0055] Preferably, the disease is selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, psoriasis, type I diabetes, myasthenia gravis, chronic inflammatory demyelinating diseases, graft-versus-host disease, ankylosing spondylitis, and axial spondyloarthritis.

[0056] Preferably, the disease is selected from ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, type I diabetes, myasthenia gravis, and graft-versus-host disease.

[0057] Preferably, the disease is selected from ulcerative colitis, rheumatoid arthritis, and multiple sclerosis.

[0058] Preferably, the tumor includes solid tumors and hematologic malignancies, especially hematologic malignancies; the hematologic malignancies include T-cell and B-cell malignancies.

[0059] Preferably, the hematologic malignancy is selected from leukemia and lymphoma.

[0060] The leukemia and lymphomas mentioned can specifically include: acute myeloid leukemia, acute lymphoblastic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, early T-cell lymphoblastic leukemia, T-cell granulocytic leukemia, aggressive NK-cell leukemia, hairy cell leukemia, nasal NK / T-cell lymphoma, mycosis fungoides and Sezary syndrome, angioimmunoblastic T-cell lymphoma, peripheral T-cell lymphoma (unspecified), adult T-cell leukemia / lymphoma, anaplastic large cell lymphoma, primary cutaneous CD30-positive T-cell lymphoproliferative disorder, cutaneous T-cell lymphoma, subcutaneous panniculitis-like T-cell lymphoma, enteropathy-type T-cell lymphoma, hepatosplenic γ / δ T-cell lymphoma, Burkitt lymphoma, chronic lymphocytic leukemia / small lymphocytic lymphoma, diffuse large B-cell lymphoma. Mantle cell lymphoma, Waldenström macroglobulinemia, follicular lymphoma, mantle cell lymphoma, mucosa-associated lymphoid tissue lymphoma.

[0061] Beneficial effects:

[0062] The compounds provided by this invention exhibit strong efficacy, favorable pharmacokinetic properties, and low toxicity, making them ideal VAV1 degrading agents (also known as VAV1 molecular gel degrading agents). This invention separates isomers based on the racemic mixture and discovers that some isomers possess significantly stronger activity. The compounds provided by this invention exhibit good VAV1 degrading activity and can enhance the degradation of VAV1 protein by strengthening the interaction between VAV1 protein and E3 ligase. Detailed Implementation

[0063] The present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited to the following embodiments.

[0064] definition

[0065] The terms "optional" or "optionally" used in this article mean that any optional option can be selected or not selected. For example, "group A is optionally replaced by 1-3 groups B" includes four cases: group A is not replaced by group B, group A is replaced by 1 group B, group A is replaced by 2 groups B, and group A is replaced by 3 groups B.

[0066] As used herein, "substitution" or "substituted" refers to the substitution of one or more hydrogen atoms on any atom of a group or segment by a substituent, which may include deuterium and hydrogen variants, provided that the valence state of the specific atom is normal and the substituted compound is stable. When the substituent is "oxo" (i.e., =O), it means that two hydrogen atoms are replaced by oxygen, and when the oxygen-substituted atom is a carbon atom, a carbonyl group (C=O) is formed. Oxygen substitution does not occur on aromatic groups. When the substituent is "=CH2", it means that two hydrogen atoms are replaced by a methylene group linked by a double bond.

[0067] As used in this article, "optionally substituted" means that it may or may not be substituted. Unless otherwise specified, the type and number of substituents can be arbitrary, provided that it is chemically feasible. For example, "optionally substituted 5-6 membered heterocyclic group" refers to a 5-6 membered heterocyclic group that is substituted or unsubstituted by any group. Another example is "optionally substituted with 1-3 R groups..." a Replacement C 1-6 "Alkyl" refers to an unsubstituted or alkyl group consisting of 1-3 R groups. a Replacement C 1-6 alkyl.

[0068] When any variable (e.g., R) appears more than once in the composition or structure of a compound, its definition is independent in each case. Thus, for example, if a group is substituted by 0-2 Rs, the group can optionally be substituted by at most two Rs, and the Rs in each case have independent options. Furthermore, combinations of substituents and / or their variants are only permitted if such combinations produce a stable compound.

[0069] The term "chemical bond" as used in this article generally refers to a covalent bond formed between two atoms in a compound molecule by sharing a pair of electrons.

[0070] When a substituent is vacant, it means that the substituent does not exist. For example, if X is vacant in AX, the structure is actually A. When the listed substituents do not specify which atom they are attached to the substituted group through, such substituents can be bonded to any of their atoms. For example, a pyridinium group as a substituent can be attached to the substituted group through any carbon atom on the pyridine ring.

[0071] Where the listed linking groups do not specify their connection direction, the connection direction is arbitrary. For example, in ring A-L1-R1, the linking group L1 is -MW-. In this case, -MW- can connect rings A and R1 in the same direction as the left-to-right reading order to form ring AMW-R1, or connect rings A and R1 in the opposite direction to the left-to-right reading order to form ring AWM-R1. Combinations of linking groups, substituents, and / or their variants are only permitted if such combinations produce a stable compound.

[0072] Unless otherwise specified, when a group has one or more connectable sites, any one or more sites of that group can be connected to other groups via chemical bonds. When the chemical bond connection is non-directional and the connectable site contains H atoms, the number of H atoms at that site will decrease accordingly with the number of chemical bonds connected, resulting in a group with the corresponding valence. The chemical bonds connecting the site to other groups can be represented by straight solid line bonds or straight “…”. "dashed key" The solid line in -OCH3 indicates that the oxygen atom in that group is connected to other groups. The straight dashed bond in the diagram indicates that the group is connected to other groups through both ends of the carbon atom in the group; The dashed lines in the diagram indicate that the phenyl group is connected to other groups through the carbon atoms at positions 1 and 4 of the phenyl group. This indicates that any connectable site on the piperidinyl group can be linked to other groups via a single chemical bond, including at least... , , , Even if H atoms are drawn on -N- in these four connection methods, Still includes In this type of linkage, when a chemical bond is attached, the number of hydrogen atoms at that site is reduced by one, resulting in a monovalent piperidinyl group.

[0073] Unless otherwise specified, in cyclic groups, the linkage site of the group or segment is located on the ring connected by the dashed line. For example, This indicates that any linking site on the benzene ring of this group can be connected to other groups by a single chemical bond, including at least... , , , These are the four connection methods.

[0074] Generally, in aromatic or heteroaromatic rings, the use of double and single bonds is not significant. For example, , , Both refer to benzene rings or phenyl groups, where double bonds or " Specifically refers to large π bonds delocalized on the plane of the benzene ring; In this context, when ring C is defined as a 5-membered aryl or heteroaryl, ring B and ring C form a conjugated cycloaryl or cycloheteroaryl group. Non-limiting embodiments include... , , , , ;even though or The left-hand ring contains only two double bonds, but Still includes or In this group, the double bond represents a large π bond delocalized on the fused aromatic ring.

[0075] The numerical ranges used in this article include the endpoints and any values ​​in between. For example, "0-3" can include 0, 1, 2, or 3, and "1-3" can include 1, 2, or 3.

[0076] The "C" used in this article 1-n "Including C" 1-2 C 1-3 ...C 1-n For example, "C" 1-6 A "group" refers to a part containing 1 to 6 carbon atoms; that is, a group may contain 1, 2, 3, 4, 5, or 6 carbon atoms. Therefore, for example, "C..." 1-4 "Alkyl" refers to an alkyl group containing 1 to 4 carbon atoms, specifically selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and tert-butyl. Numerical ranges, such as "1-6", refer to integers within a given range.

[0077] A linker atom refers to a non-hydrogen atom in a cyclic group that is used for ring formation. For example... The atom in the link consists of 3 carbon atoms; The middle element consists of three carbon atoms and one oxygen atom; The intermediate atom consists of 1 nitrogen atom and 5 carbon atoms; The middle element consists of 8 carbon atoms and 1 nitrogen atom.

[0078] As used herein, "nm-membered" refers to the number of link atoms in a cycloalkyl group. For example, a "3-8 membered" group means that the part has 3-8 link atoms, that is, the group contains 3, 4, 5, 6, 7, or 8 link atoms. Therefore, for example, "3-8 membered cycloalkyl" refers to a saturated cycloalkyl group containing 3-8 carbon atoms, that is, the alkyl group is selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.

[0079] The term "alkyl" as used alone or in combination herein refers to a saturated aliphatic hydrocarbon that is optionally substituted with a straight chain or optionally substituted with a branched chain. "alkyl" as used herein preferably has 1-6 carbon atoms, for example, 1-5 carbon atoms, 1-4 carbon atoms, or 1-3 carbon atoms. Non-limiting examples of alkyl groups include methyl, ethyl, n-propyl, isopropyl, 2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl, 3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl, 2-methyl-1-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl, 2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl, 2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, etc. In this document, when the term "alkyl" is used in a numerical range, such as "C1-6 alkyl," it refers to an alkyl group that can be composed of 1, 2, 3, 4, 5, or 6 carbon atoms. The term alkyl in this document also includes cases where no numerical range is specified. Alkyl groups can be optionally substituted or unsubstituted.

[0080] The term “alkyl” as used in this article refers to an alkyl group linked to other groups, such as an alkyl group in an alkoxy group, and is defined the same as when used alone.

[0081] The term "alkoxy" or "-O-alkyl" as used alone or in combination herein is meant as "alkyl-O-". Non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, etc. Alkoxy groups may be optionally substituted or unsubstituted.

[0082] The term "cycloalkyl" as used alone or in combination herein refers to a saturated monocyclic, bicyclic, or polycyclic carbon ring. Preferably, it is a 3-12 membered cycloalkyl, more preferably a 3-10 membered cycloalkyl, and most preferably a 3-8 membered cycloalkyl. Non-limiting examples of monocyclic cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and other cycloalkyl groups, which may be optionally substituted or unsubstituted.

[0083] The term "aryl" as used alone or in combination herein refers to an aromatic hydrocarbon ring. The term "aryl" includes monocyclic aromatic hydrocarbons and polycyclic fused-ring (fused-ring) aromatic hydrocarbons, wherein all fused-ring systems (excluding any ring system that is part of an optional substituent or formed by an optional substituent) are aromatic. Examples of aryl groups / parts include phenyl, naphthyl, anthraceneyl, and phenanthrene. Unless otherwise stated, the term "aryl" does not include "heteroaryl".

[0084] The term "heterocyclic group" as used alone or in combination herein includes alicyclic and heteroaryl groups, wherein one or more (such as one, two, three, or four) link atoms are heteroatoms, such as oxygen, nitrogen, sulfur, etc., including monocyclic, fused, bridged, and spirocyclic groups. Examples of heterocyclic groups include heterocyclic alkyl, heterocyclic alkenyl, and heteroaryl groups discussed below. Preferably, 3- to 10-membered monocyclic, bicyclic, or tricyclic heterocyclic groups are used herein, which may contain one, two, or three link atoms selected from nitrogen, oxygen, and / or sulfur. Non-limiting examples of "heterocyclic group" include azirrobutenyl, azirrobutyl, oxobutyl, thiobutyl, pyrrolyl, 2-oxo-pyrrolyl, tetrahydrofuranyl, tetrahydrothiophenyl, pyrazolyl, imidazoyl, dioxacyclopentyl, oxothiopentyl, piperidinyl, 2-oxo-piperidinyl, tetrahydropyranyl, thioalkyl, piperazinyl, piperazine-2-one, dioxacyclohexyl, morpholinyl and thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, etc. The heterocyclic group may be optionally substituted or unsubstituted.

[0085] In the definition of "heterocyclic group," "fused ring" refers to a polycyclic cyclic group containing two or more ring structures that share a pair of atoms. One or more rings may contain several unsaturated bonds, or it may be an aromatic system with one ring having fully conjugated π electrons. The ring atoms are selected from nitrogen, oxygen, or S(O). n (where n is selected from 0, 1, or 2) heteroatoms, and the remaining atoms are carbon. Preferably, they are 6-12 cyclic, more preferably 8-9 cyclic. Based on the number of rings, they can be classified as bicyclic, tricyclic, tetracyclic, or polycyclic cyclic groups, preferably bicyclic or tricyclic, more preferably 5-membered / 5-membered or 5-membered / 6-membered bicyclic cyclic groups.

[0086] The term "heterocyclic alkyl" as used alone or in combination herein refers to a saturated heterocyclic group, which is a monocyclic, bicyclic, or polycyclic alkyl group in which one or more (such as one, two, three, or four) link atoms are heteroatoms, and may be spirocyclic or bridged. Preferably, it is a 3-12 membered cycloalkyl group, more preferably a 3-10 membered cycloalkyl group, and most preferably a 3-8 membered cycloalkyl group. Non-limiting examples of monocyclic heterocyclic alkyl groups include, but are not limited to, propylene oxide, thiocyclic propane, azirionic propane, azirionic butane, oxacyclobutane, thiocyclic butane, tetrahydrofuran, tetrahydrothiophene, tetrahydropyrrole, oxazolidine, thiazolylidine, imidazolylidine, tetrahydropyran, piperidine, dioxane, and azirionic heptane.

[0087] The term "heteroaryl" as used alone or in combination herein refers to a 5-12 member (preferably 5-10 member, more preferably 5-6 member) monocyclic, bicyclic, or tricyclic system, wherein at least one ring is aromatic and at least one ring contains one or more heteroatoms selected from nitrogen, oxygen, and sulfur, and the heteroaryl group has one or more attachment sites connected to the remainder of the molecule. Non-limiting examples of "heteroaryl" include furanyl, imidazolyl, isoxazolyl, oxazolyl, pyrroleyl, pyrazolyl, pyridinyl, pyrimidinyl, pyridazinyl, thiophene, thiazolyl, etc.; it also includes, but is not limited to, the following bicyclic groups: benzimidazolyl, benzofuranyl, benzothiophene, indolyl, oxoindolyl, dihydroindolyl, imidazopyridyl, pyrazolopyridyl, pyrazolopyrimidinyl, quinolinyl, isoquinolinyl, quinazolinyl, indazole, 1,8-naphthidine, benzo[d]isoxazole, benzo[ [d]Thiazole, pyrrolo[3,2-b]pyridine, furan[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, imidazo[1,2-b]pyridazine, pyrazolo[1,5-a]pyrimidine, thiazo[4,5-c]pyridine, thieno[3,2-b]pyridine, pyrrolo[1,2-b]pyridazine, 2,3-dihydrobenzofuran, benzo[c][1,2,5]oxadiazole, 1,3-dihydro-2H-benzo[d]imidazo-2-one, benzo[d]oxazol-2(3H)-one, etc. The heteroaryl group can be optionally substituted or unsubstituted.

[0088] The term “halogen” as used alone or in combination in this article refers to fluorine, chlorine, bromine or iodine.

[0089] The term "hydroxyl group" as used alone or in combination in this article refers to -OH.

[0090] The term "cyano" as used alone or in combination in this article refers to -CN.

[0091] As used herein, the terms “(substituted)” or “substituted with” refer to the substitution of one or more hydrogen atoms on a particular atom by a specified group (such as halogen, alkyl, etc.) where the substitution results in a stable compound if the normal valence of the specified atom is not exceeded under the present circumstances.

[0092] The term “pharmaceutically acceptable salt” as used herein is well known to those skilled in the art.

[0093] As used herein, the term "pharmaceutically acceptable" means a substance (such as a carrier or diluent) that does not affect the biological activity or properties of the compounds of the present invention and is relatively non-toxic, i.e., that the substance can be administered to an individual without causing an adverse biological reaction or interacting adversely with any component contained in the composition.

[0094] As used herein, the term "pharmaceutical composition" refers to a bioactive compound optionally mixed with at least one pharmaceutically acceptable chemical component, including but not limited to carriers, stabilizers, diluents, dispersants, suspending agents, thickeners, and / or excipients.

[0095] As used in this article, the term "carrier" refers to a relatively non-toxic chemical compound or reagent that facilitates the introduction of the compound into cells or tissues.

[0096] The term “stereoisomer” as used in this article includes, but is not limited to, enantiomers, cis-trans isomers, etc.

[0097] As used herein, the term "enantiomer" refers to isomerism in compounds with the same molecular formula, resulting from differences in the spatial arrangement of atoms or groups. Two enantiomers are mirror images of each other and cannot be superimposed. The term "cis-trans isomer" as used herein generally refers to stereoisomerism, a non-diasteretic phenomenon where the spatial arrangement of groups differs due to rotational constraints within the molecule. Organic molecules containing such isomers, such as alkenes, azo compounds, and alicyclic hydrocarbons, are considered cis-trans isomers. In this application, cis-trans isomerism is primarily manifested in alicyclic hydrocarbons. For example, in cyclohexane, cis-trans isomerism occurs when two substituents are substituted. When the two substituents are substituted on the same side of the ring, it is a "cis" isomer; when they are substituted on different sides, it is a "trans" isomer.

[0098] The compounds of this invention may contain asymmetric or chiral centers, and thus exist in different stereoisomer forms. It is contemplated that all stereoisomer forms of the compounds of this invention, including but not limited to diastereomers, enantiomers, sterically hindered isomers, and geometric (conformal) isomers and mixtures thereof, such as racemic mixtures, are within the scope of this invention.

[0099] Unless otherwise stated, the structures described in this invention also include all isomers of this structure (e.g., diastereomers, enantiomers, cis-trans isomers, sterically hindered isomers, geometric (conformal) isomers), for example, R and S configurations of each asymmetric center, (Z) and (E) double bond isomers, cis-trans isomers of aliphatic cyclic hydrocarbons, sterically hindered isomers of biphenyl structures (see *Basic Organic Chemistry* (Second Edition), Vol. 1, Xing Qiyi et al., pp. 104-105); PAC, 1996, 68, 2193. (*Basic terminology of stereochemistry* (IUPAC Recommendations 1996, on page 2201)), and (Z) and (E) conformational isomers. Therefore, individual stereoisomers of the compounds of this invention, as well as mixtures of enantiomers, mixtures of diastereomers, sterically hindered isomers, and mixtures of geometric (conformal) isomers, are all within the scope of this invention.

[0100] The present invention will be further described in detail below with reference to specific embodiments, but the present invention is not limited to the following embodiments.

[0101] The preparation conditions used in the examples are as follows:

[0102] Prep-HPLC preparation conditions: Instrument: GILSON-GX281; Wavelength: 220 nm & 254 nm; Column type: Waters X-bridge (30×100 mm, 10 μm) or Luna C18 (30×75 mm, 3 μm) or Luna C18 (30×75 mm, 3 μm); Mobile phase: A: 10 mM ammonium bicarbonate or H2O (0.1% formic acid) or H2O (0.1% trifluoroacetic acid), B: acetonitrile; Run time: 15 min; Flow rate: 25 mL / min.

[0103] Reverse-phase column purification was performed using a C18 reverse-phase silica column (Spherical C18, 40-60 μm, 40 g-120 g) with water / acetonitrile (95 / 5~30 / 70) as the mobile phase.

[0104] Chiral separation conditions 1: Instrument: SFC 150; Column type: Daicel CHIRALPAK IB-N, 250 mm × 30 mm inner diameter, 10 μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7M methanol solution)] = 50 / 50; Flow rate: 120 g / min; Wavelength: UV 214 nm; Temperature: 35℃.

[0105] Chiral separation conditions 2: Instrument: SFC 150; Column type: Daicel CHIRALCEL OD, 250 mm × 30 mm inner diameter, 10 μm; Mobile phase: CO2 / MeOH [0.2% NH3 (7M methanol solution)] = 60 / 40; Flow rate: 120 g / min; Wavelength: UV 214 nm; Temperature: 35℃.

[0106] The synthesis steps of some intermediates in this invention are as follows:

[0107] Intermediate 1: 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione

[0108]

[0109] (1) 1-Bromo-3-(bromomethyl)-2-chlorobenzene

[0110] 1-Bromo-2-chloro-3-toluene (5 g, 24.3 mmol) and N-bromosuccinimide (4.8 g, 27.0 mmol) were dissolved in carbon tetrachloride (50 mL), and then benzoyl peroxide (0.3 g, 1.2 mmol) was added. The mixture was stirred at 90 °C under reflux for 16 hours. The reaction solution was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (100% petroleum ether) to give the title compound (3.8 g, colorless oil), yield: 55%. 1 H NMR (400 MHz, CDCl3) δ 7.60-7.55(m, 1H), 7.40-7.36 (m, 1H), 7.13-7.06 (m, 1H), 4.61-4.59 (m, 2H).

[0111] (2) 2-(3-bromo-2-chlorophenyl)acetonitrile

[0112] 1-Bromo-3-(bromomethyl)-2-chlorobenzene (3.8 g, 13.4 mmol) was dissolved in dichloromethane (40 mL), and trimethylcyanosilane (1.99 g, 20.1 mmol) and tetrabutylammonium fluoride (20.1 mL, 20.1 mmol, 1 M inTHF) were added at 0 °C, followed by stirring at room temperature for 4 hours. The reaction mixture was extracted with water (100 mL), ethyl acetate (50 x 3 mL), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 90 / 10) to give the title compound (2.8 g, white solid), yield: 90%. 1H NMR (400 MHz, CDCl3) δ7.66-7.62 (m, 1H), 7.50-7.47 (m, 1H), 7.21-7.18 (m, 1H), 3.89-3.87 (m, 2H).

[0113] (3) tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate

[0114] 2-(3-bromo-2-chlorophenyl)acetonitrile (2.5 g, 10.8 mmol) was dissolved in tetrahydrofuran (25 mL), and potassium tert-butoxide (0.12 g, 2.2 mmol) and tert-butyl acrylate (1.38 g, 10.8 mmol) were added at 0 °C. The mixture was then stirred at room temperature for 2 hours. The reaction mixture was extracted with water (100 mL), ethyl acetate (50 x 3 mL), washed with saturated sodium chloride solution (100 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by reverse-phase column chromatography to give the title compound (1.5 g, pale yellow oil), yield: 39%. MS (ESI): m / z 358.0 [M+H] + .

[0115] (4) 3-(3-bromo-2-chlorophenyl)piperidine-2,6-dione

[0116] 1.5 g (4.2 mmol) of tert-butyl 4-(3-bromo-2-chlorophenyl)-4-cyanobutyrate and 2.06 g (21 mmol) of concentrated sulfuric acid were dissolved in acetic acid (15 mL) and stirred at room temperature for 1 hour. The reaction mixture was then slowly added dropwise to ice water (100 mL), resulting in the precipitation of a white solid. The precipitate was filtered to give the title compound (1.4 g, white solid), yield: 95%. MS (ESI): m / z 302.0 [M+H] + .

[0117] Intermediate 2: 3-(2-chloro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborhecyclopentan-2-yl)phenyl)piperidin-2,6-dione

[0118]

[0119] Intermediate 1 (300 mg, 1.0 mmol), pinacol diborate (330.2 mg, 1.3 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (36.6 mg, 0.05 mmol), and potassium acetate (294.4 mg, 3.0 mmol) were dissolved in 1,4-dioxane (5 mL), and the mixture was stirred at 80 °C under nitrogen protection for 3 hours. The reaction solution was cooled to give the title compound, which was used directly in the next reaction. MS (ESI): m / z 350.1 [M+H] + .

[0120] Intermediate 3: N-(4-bromophenyl)-N-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-amine

[0121]

[0122] (1) N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0123] 1-Bromo-4-iodobenzene (2 g, 7.1 mmol), 1-methyl-1H-1,2,4-triazol-3-amine (0.7 g, 7.1 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (0.8 g, 1.4 mmol), tris(dibenzylacetone)dipalladium (0.6 g, 0.7 mmol), and cesium carbonate (5.78 g, 17.8 mmol) were dissolved in 1,4-dioxane (30 mL), and the mixture was purged with nitrogen. The reaction mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 98 / 2) to give the title compound (230 mg, yellow solid), yield: 87%. MS (ESI): m / z 253.0 [M+H] + .

[0124] (2) N-(4-bromophenyl)-N-cyclopropyl-1-methyl-1H-1,2,4-triazol-3-amine

[0125] N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (400 mg, 1.58 mmol) and cyclopropylboronic acid (272 mg, 3.16 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2,2'-bipyridine (247 mg, 1.58 mmol), copper acetate (287 mg, 1.58 mmol), and potassium carbonate (437 mg, 3.16 mmol) were added. The mixture was stirred at 120 °C for 22 hours under oxygen bulb conditions. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (dichloromethane / methanol = 95 / 5) to give the title compound (100 mg, yellow oil), yield: 22%. MS (ESI): m / z 293.0 [M+H] + .

[0126] Intermediate 4: N-(4-bromophenyl)-N-cyclopropyl-5-methoxypyrimidine-2-amine

[0127]

[0128] (1) N-(4-bromophenyl)-5-methoxypyrimidine-2-amine

[0129] 1-Bromo-4-iodobenzene (300 mg, 1.06 mmol) and 5-methoxypyrimidin-2-amine (133 mg, 1.06 mmol) were dissolved in 1,4-dioxane (10 mL), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (123 mg, 0.21 mmol), tris(dibenzylacetone)dipalladium (97 mg, 0.11 mmol), and cesium carbonate (864 mg, 2.65 mmol) were added. The mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give the title compound (210 mg, yellow solid), yield: 70.7%. MS (ESI): m / z 280.0 [M+H] + .

[0130] (2) N-(4-bromophenyl)-N-cyclopropyl-5-methoxypyrimidin-2-amine

[0131] N-(4-bromophenyl)-5-methoxypyrimidine-2-amine (210 mg, 0.75 mmol) and cyclopropylboronic acid (129 mg, 1.5 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (117 mg, 0.75 mmol), copper acetate (136 mg, 0.75 mmol), and potassium carbonate (207 mg, 1.5 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen bulb. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (120 mg, pale yellow solid), yield: 20%. MS (ESI): m / z 320.0 [M+H] + .

[0132] Intermediate 5: N-(4-bromophenyl)-N-cyclopropyl-5-methylpyrimidin-2-amine

[0133]

[0134] (1) N-(4-bromophenyl)-5-methylpyrimidin-2-amine

[0135] 1-Bromo-4-iodobenzene (300 mg, 1.06 mmol) and 5-methylpyrimidin-2-amine (116 mg, 1.06 mmol) were dissolved in 1,4-dioxane (10 mL), and 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (123 mg, 0.21 mmol), tris(dibenzylacetone)palladium (97 mg, 0.11 mmol), and cesium carbonate (864 mg, 2.65 mmol) were added. The mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 70 / 30) to give the title compound (220 mg, yellow solid), yield: 78.6%. MS (ESI): m / z 264.0 [M+H] + .

[0136] (2) N-(4-bromophenyl)-N-cyclopropyl-5-methylpyrimidin-2-amine

[0137] N-(4-bromophenyl)-5-methylpyrimidin-2-amine (220 mg, 0.83 mmol) and cyclopropylboronic acid (143 mg, 1.67 mmol) were dissolved in dichloroethane (5 mL), and 2,2'-bipyridine (130 mg, 0.83 mmol), copper acetate (151 mg, 0.83 mmol), and potassium carbonate (230 mg, 1.67 mmol) were added. The mixture was stirred overnight at 80 °C under an oxygen bulb. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (110 mg, pale yellow solid), yield: 21.7%. MS (ESI): m / z 304.1 [M+H] + .

[0138] Intermediate 6: N-(4-bromophenyl)-N-(2,2-difluoroethyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0139]

[0140] N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (150 mg, 0.6 mmol, intermediate 3, step 1) and cesium carbonate (391 mg, 1.2 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 1,1-difluoro-2-iodoethane (172 mg, 0.9 mmol) was added. The mixture was stirred overnight at 130 °C. The reaction solution was added to water (10 mL), and extracted with ethyl acetate (10 mL x 3). The organic phases were combined and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 5 / 1) to give the title compound (20 mg, yellow oil), yield: 11%. MS (ESI): m / z 317.0 [M+H] + .

[0141] Intermediate 7: N-(4-bromophenyl)-N-cyclopropyl-1-(difluoromethyl)-1H-1,2,4-triazol-3-amine

[0142]

[0143] (1) 1-(difluoromethyl)-3-nitro-1H-1,2,4-triazole

[0144] 3-Nitro-1H-1,2,4-triazole (300 mg, 2.6 mmol) and sodium 2-chloro-2,2-difluoroacetate (400 mg, 9.8 mmol) were dissolved in N,N-dimethylformamide (5 mL), and potassium carbonate (718 mg, 5.2 mmol) was added. The mixture was stirred in a microwave at 120 °C for 3 hours. Water (20 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (15 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (280 mg, yellow oil), yield: 65%. MS (ESI): m / z 165.0 [M+H] + .

[0145] (2) 1-(difluoromethyl)-1H-1,2,4-triazol-3-amine

[0146] 1-(difluoromethyl)-3-nitro-1H-1,2,4-triazole (200 mg, 1.2 mmol) and iron powder (269 mg, 4.8 mmol) were dissolved in ethanol / water (10 mL / 2 mL), and ammonium chloride (254 mg, 4.8 mmol) was added. The mixture was stirred at 80 °C for 1 hour. The reaction solution was filtered through diatomaceous earth, the filtrate was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (100 mg, yellow solid), yield: 63%. MS (ESI): m / z 135.2 [M+H] + .

[0147] (3) N-(4-bromophenyl)-1-(difluoromethyl)-1H-1,2,4-triazol-3-amine

[0148] 1-Bromo-4-iodobenzene (200 mg, 0.72 mmol), 1-(difluoromethyl)-1H-1,2,4-triazol-3-amine (100 mg, 0.72 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (80 mg, 0.14 mmol), tris(dibenzylacetone)dipalladium (64 mg, 0.07 mmol), and cesium carbonate (456 mg, 1.4 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen and stirred overnight at 90 °C under nitrogen protection. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (150 mg, yellow solid), yield: 72%. MS (ESI): m / z 289.1 [M+H] + .

[0149] (4) N-(4-bromophenyl)-N-cyclopropyl-1-(difluoromethyl)-1H-1,2,4-triazol-3-amine

[0150] N-(4-bromophenyl)-1-(difluoromethyl)-1H-1,2,4-triazol-3-amine (70 mg, 0.24 mmol) and cyclopropylboronic acid (41 mg, 0.48 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (37 mg, 0.24 mmol), copper acetate (44 mg, 0.24 mmol), and potassium carbonate (66 mg, 0.48 mmol) were added. The mixture was heated to 120 °C and stirred overnight under oxygen bulb conditions. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (50 mg, yellow oil), yield: 63%. MS (ESI): m / z 329.0 [M+H] + .

[0151] Intermediate 8: N-(4-bromophenyl)-N-cyclopropyl-1-(methyl-d3)-1H-1,2,4-triazol-3-amine

[0152]

[0153] Following the synthetic method for intermediate 3, in step 1, 1-methyl-1H-1,2,4-triazol-3-amine was replaced with 1-(methyl-d3)-1H-1,2,4-triazol-3-amine, and the title compound was obtained through similar synthetic steps. MS (ESI): m / z 296.1 [M+H] + .

[0154] Intermediate 9: N-(4-bromophenyl)-N-cyclopropyl-5-(difluoromethyl)pyrimidin-2-amine

[0155]

[0156] (1) N-(4-bromophenyl)-5-(difluoromethyl)pyrimidin-2-amine

[0157] p-Bromoaniline (50 mg, 0.29 mmol) and 2-chloro-5-(difluoromethyl)pyrimidine (48 mg, 0.29 mmol) were dissolved in 1,4-dioxane / acetic acid (3 mL / 1 mL) and reacted with stirring at 110 °C for 16 h. Water (30 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 85 / 15) to give the title compound (65 mg, pale yellow solid), yield: 67%. MS (ESI): m / z 300.0 [M+H] + .

[0158] (2) N-(4-bromophenyl)-N-cyclopropyl-5-(difluoromethyl)pyrimidin-2-amine

[0159] N-(4-bromophenyl)-5-(difluoromethyl)pyrimidin-2-amine (65 mg, 0.22 mmol) and cyclopropylboronic acid (37 mg, 0.43 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2,2'-bipyridine (34 mg, 0.22 mmol), copper acetate (39 mg, 0.22 mmol), and potassium carbonate (60 mg, 0.43 mmol) were added. The mixture was heated to 120 °C and stirred for 48 hours under oxygen bulb conditions. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 92 / 8) to give the title compound (58 mg, white solid), yield: 79%. MS (ESI): m / z 340.0 [M+H] + .

[0160] Intermediate 10: N-(4-bromophenyl)-N-cyclopropyl-1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-amine

[0161]

[0162] Following the synthetic method for intermediate 3, in step 1, 1-methyl-1H-1,2,4-triazol-3-amine was replaced with 1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-amine, and the title compound was obtained through similar synthetic steps. MS (ESI): m / z 333.1 [M+H] + .

[0163] Intermediate 11: N-(4-bromophenyl)-N-cyclopropyl-5-(difluoromethoxy)pyrimidine-2-amine

[0164]

[0165] (1) N-(4-bromophenyl)-5-(difluoromethoxy)pyrimidin-2-amine

[0166] 4-Bromoaniline (400 mg, 2.33 mmol), 2-chloro-5-(difluoromethoxy)pyrimidine (420 mg, 2.33 mmol), and cesium carbonate (1.52 mg, 4.66 mmol) were dissolved in N,N-dimethylformamide (10 mL) and reacted with stirring at 130 °C for 16 h. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (20 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (30 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by reversed-phase column chromatography (acetonitrile / water = 70 / 30) to give the title compound (230 mg, brown solid), yield: 31%. MS (ESI): m / z 316.0 [M+H] + .

[0167] (2) N-(4-bromophenyl)-N-cyclopropyl-5-(difluoromethoxy)pyrimidin-2-amine

[0168] N-(4-bromophenyl)-5-(difluoromethoxy)pyrimidine-2-amine (230 mg, 0.73 mmol) and cyclopropylboronic acid (125 mg, 1.46 mmol) were dissolved in N,N-dimethylformamide (10 mL), and 2,2'-bipyridine (114 mg, 0.73 mmol), copper acetate (132 mg, 0.73 mmol), and potassium carbonate (201 mg, 1.46 mmol) were added. The mixture was stirred at 120 °C for 24 hours under oxygen bulb conditions. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 93 / 7) to give the title compound (100 mg, pale yellow oil), yield: 39%. MS (ESI): m / z 356.0 [M+H] + .

[0169] Intermediate 12: N-(4-bromophenyl)-N-(cyclopropylmethyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0170]

[0171] N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (100 mg, 0.40 mmol, intermediate 3, step 1) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (32 mg, 0.79 mol) was added at 0 °C and the mixture was stirred for 0.5 h. Then (bromomethyl)cyclopropane (53 mg, 0.40 mmol) was added, and the mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (100 mg, pale yellow oil), yield: 82%. MS (ESI): m / z 307.1 [M+H] + .

[0172] Intermediate 13: N-(4-bromophenyl)-N-((1-fluorocyclopropyl)methyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0173]

[0174] (1) Methyl (1-fluorocyclopropyl)methanesulfonate

[0175] (1-Fluorocyclopropyl)methanol (200 mg, 2.66 mmol) and triethylamine (674 mg, 6.66 mol) were dissolved in dichloromethane (5 mL). Methylsulfonyl chloride (303 mg, 2.66 mol) was added at 0 °C, and the mixture was stirred at room temperature for 0.5 h. The reaction solution was concentrated to give the title compound (373 mg, white solid), yield: 100%. 1 H NMR (400 MHz, CDCl3) δ 4.48 (d, J = 22.0 Hz, 1H), 3.11 (s, 3H), 1.30-1.16 (m, 2H), 0.93-0.79 (m, 2H).

[0176] (2) N-(4-bromophenyl)-N-((1-fluorocyclopropyl)methyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0177] N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (250 mg, 0.99 mmol, intermediate 3, step 1) was dissolved in N,N-dimethylformamide (5 mL). Sodium hydride (79 mg, 1.98 mmol) was added at 0 °C and the mixture was stirred for 0.5 h. Then, methyl (1-fluorocyclopropyl)methanesulfonate (166 mg, 0.99 mmol) was added, and the mixture was stirred at 70 °C for 16 h. The reaction mixture was diluted with water (50 mL) and extracted with ethyl acetate (30 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (50 mg, pale yellow oil), yield: 16%. MS (ESI): m / z 325.0 [M+H] + .

[0178] Intermediate 14: N-(4-bromophenyl)-1-(cyclopropylmethyl)-N-(2,2-difluoroethyl)-1H-1,2,4-triazol-3-amine

[0179]

[0180] N-(4-bromophenyl)-1-(cyclopropylmethyl)-1H-1,2,4-triazol-3-amine (50 mg, 0.17 mmol) and 1,1-difluoro-2-iodoethane (66 mg, 0.34 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (20 mg, 0.51 mmol) was added. The mixture was stirred overnight at 70 °C. Water (10 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (40 mg, colorless oil), yield: 67%. MS (ESI): m / z 357.0 [M+H] + .

[0181] Intermediate 15: N-(4-bromophenyl)-N-(3,3-difluorocyclobutyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0182]

[0183] (1) N-(3,3-difluorocyclobutyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0184] 3-Bromo-1-methyl-1H-1,2,4-triazole (1 g, 6.2 mmol), 3,3-difluorocyclobutane-1-amine (1.3 g, 12.4 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (720 mg, 1.2 mmol), tris(dibenzylacetone)dipalladium (550 mg, 0.6 mmol), and cesium carbonate (4 g, 12 mmol) were dissolved in 1,4-dioxane (10 mL), and the mixture was purged with nitrogen and stirred overnight at 120 °C under nitrogen protection. The reaction mixture was concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (260 mg, yellow oil), yield: 22%. MS (ESI): m / z 189.2 [M+H] + .

[0185] (2) N-(4-bromophenyl)-N-(3,3-difluorocyclobutyl)-1-methyl-1H-1,2,4-triazol-3-amine

[0186] N-(3,3-difluorocyclobutyl)-1-methyl-1H-1,2,4-triazol-3-amine (100 mg, 0.53 mmol) and (4-bromophenyl)boronic acid (213 mg, 1 mmol) were dissolved in N,N-dimethylformamide (5 mL), and 2,2'-bipyridine (83 mg, 0.53 mmol), copper acetate (96 mg, 0.53 mmol), and potassium carbonate (146 mg, 1 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen bulb. Water (10 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 1 / 1) to give the title compound (10 mg, yellow oil), yield: 6%. MS (ESI): m / z 343.0 [M+H] + .

[0187] Intermediate 16: N-(4-bromophenyl)-N-cyclopropyl-1-((1-fluorocyclopropyl)methyl)-1H-1,2,4-triazol-3-amine

[0188]

[0189] Following the synthetic method for intermediate 3, in step 1, 1-methyl-1H-1,2,4-triazol-3-amine was replaced with 1-((1-fluorocyclopropyl)methyl)-1H-1,2,4-triazol-3-amine, and the title compound was obtained through similar synthetic steps. MS (ESI): m / z 351.1 [M+H] + .

[0190] Intermediate 17: N-(4-bromophenyl)-N,1-dicyclopropyl-1H-1,2,4-triazol-3-amine

[0191]

[0192] (1) 3-Iodo-1-cyclopropyl-1H-1,2,4-triazole

[0193] 3-Iodo-1H-1,2,4-triazole (900 mg, 4.6 mmol) was dissolved in 1,2-dichloroethane (20 mL), and 2,2-bipyridine (721 mg, 4.6 mmol), cyclopropylboronic acid (793 mg, 9.2 mmol), acetone (838 mg, 4.6 mmol), and potassium carbonate (1.28 g, 9.2 mmol) were added. The reaction mixture was stirred overnight at 80 °C under an oxygen atmosphere. The reaction solution was diluted with dichloromethane (50 mL) and filtered. The filtrate was washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 80 / 20) to give the title compound (237 mg, pale yellow oil), yield: 21.8%. MS (ESI): m / z 236.0 [M+H] + .

[0194] (2) N-(4-bromophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine

[0195] 3-Iodo-1-cyclopropyl-1H-1,2,4-triazole (200 mg, 0.85 mmol) was dissolved in 1,4-dioxane (10 mL), and tris(dibenzylacetone)dipalladium (39 mg, 0.043 mmol), 4,5-bis(diphenylphosphine-9,9-dimethyloxanthracene) (49 mg, 0.085 mmol), p-bromoaniline (176 mg, 1 mmol), and cesium carbonate (832 mg, 2.55 mmol) were added. The mixture was stirred overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 50 / 50) to give the title compound (140 mg, pale yellow solid), yield: 58.9%. MS (ESI): m / z 279.1 [M+H] + .

[0196] (3) N-(4-bromophenyl)-N,1-dicyclopropyl-1H-1,2,4-triazol-3-amine

[0197] N-(4-bromophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine (140 mg, 0.5 mmol) was dissolved in N,N-dimethylformamide (5 mL), and cyclopropylboronic acid (86 mg, 1 mmol), acetone (91 mg, 0.5 mmol), 2,2'-bipyridine (78 mg, 0.5 mmol), and potassium carbonate (139 mg, 1 mmol) were added. The mixture was stirred overnight at 120 °C under an oxygen atmosphere. The reaction solution was diluted with ethyl acetate (30 mL). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 60 / 40) to give the title compound (25 mg, pale yellow oil), yield: 15.6%. MS (ESI): m / z 319.1 [M+H] + .

[0198] Intermediate 18: N-(4-bromophenyl)-1-methyl-N-(oxetane-3-yl)-1H-1,2,4-triazol-3-amine

[0199]

[0200] N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (100 mg, 0.39 mmol, intermediate 3, step 1) and 3-iodooxetine (144 mg, 0.78 mmol) were dissolved in N,N-dimethylformamide (5 mL), and sodium hydride (48 mg, 1.2 mmol) was added. The mixture was stirred overnight at 70 °C. Water (10 mL) was added to the reaction mixture, and the solution was extracted with ethyl acetate (10 mL x 3). The organic phases were combined, concentrated, and the residue was purified by silica gel column chromatography (100% ethyl acetate) to give the title compound (60 mg, white solid), yield: 49.8%. MS (ESI): m / z 309.0 [M+H] + .

[0201] Intermediate 19: N-(4-bromophenyl)-1-cyclopropyl-N-(oxetane-3-yl)-1H-1,2,4-triazol-3-amine

[0202]

[0203] N-(4-bromophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine (50 mg, 0.18 mmol, intermediate 17, step 2), N,N-dimethylformamide (4 mL), 3-iodooxetine (66 mg, 0.36 mmol), and sodium hydride (22 mg, 0.54 mmol, 60%) were added to a 20 mL sealed tube and the mixture was stirred overnight at 100 °C under nitrogen protection. The reaction mixture was poured into saturated brine (50 mL) and extracted with ethyl acetate (2 x 30 mL). The organic phases were combined, washed with saturated brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to give the title compound (32 mg, pale yellow oil), yield: 53%. MS (ESI): m / z 335.1 [M+H] + .

[0204] Intermediate 20: N-(4-bromophenyl)-1-cyclopropyl-N-(oxetane-3-yl)-1H-1,2,4-triazol-3-amine

[0205]

[0206] Following the synthetic method for intermediate 6, N-(4-bromophenyl)-1-cyclopropyl-1H-1,2,4-triazol-3-amine was replaced with N-(4-bromophenyl)-1-methyl-1H-1,2,4-triazol-3-amine (step 2 of intermediate 17), and the title compound was obtained through similar synthetic steps. MS (ESI): m / z 343.1 [M+H] + .

[0207] Example 1

[0208] (S)-3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (1-01) and (R)-3-(2-chloro-4'-(cyclopropyl(1-methyl-1H-1,2,4-triazol-3-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (1-02)

[0209] and

[0210] Intermediate 3 (200 mg, 0.68 mmol), intermediate 2 (240 mg, 0.68 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (52 mg, 0.08 mmol), and potassium carbonate (240 mg, 1.72 mmol) were dissolved in 1,4-dioxane / water (10 mL / 1 mL), and the mixture was stirred at 80 °C under nitrogen protection for 16 hours. Water (100 mL) was added to the reaction mixture, and the mixture was extracted with ethyl acetate (50 mL x 3). The organic phases were combined, washed with saturated sodium chloride solution (20 mL), dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by silica gel column chromatography (dichloromethane / methanol = 98 / 2) to give a racemic compound (155 mg, white solid), yield: 52%.

[0211] The racemic compound (100 mg) was prepared by chiral separation (chiral separation condition 1) to obtain compound 1-01 (48.2 mg, white solid) and compound 1-02 (41.7 mg, white solid). The absolute configuration was not determined.

[0212] Example compound 1-01 (corresponding to compounds with shorter retention times): MS (ESI): m / z 436.2 [M+H] + . 1 HNMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.31 (s, 1H), 7.40-7.28 (m, 7H), 4.34 (dd, J = 12.0, 4.8 Hz, 1H), 3.82 (s, 3H), 2.96-2.89 (m, 1H), 2.84-2.73(m, 1H), 2.60-2.53 (m, 1H), 2.38-2.29 (m, 1H), 2.09-2.00 (m, 1H), 0.98-0.89(m, 2H), 0.61-0.51 (m, 2H).

[0213] Example compound 1-02 (corresponding to compounds with longer retention times): MS (ESI): m / z 436.2 [M+H] + . 1HNMR (400 MHz, DMSO-d6) δ 10.91 (s, 1H), 8.31 (s, 1H), 7.39-7.28 (m, 7H), 4.34 (dd, J = 12.0, 4.8 Hz, 1H), 3.82 (s, 3H), 2.98-2.90 (m, 1H), 2.87-2.71(m, 1H), 2.59-2.53 (m, 1H), 2.38-2.29 (m, 1H), 2.08-2.00 (m, 1H), 0.99-0.89(m, 2H), 0.60-0.51 (m, 2H).

[0214] Example 2

[0215] (S)-3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (2-01) and (R)-3-(2-chloro-4'-(cyclopropyl(5-methoxypyrimidin-2-yl)amino)-[1,1'-biphenyl]-3-yl)piperidin-2,6-dione (2-02)

[0216] and

[0217] Intermediate 4 (200 mg, 0.62 mmol), intermediate 3 (219 mg, 0.62 mmol), [1,1'-bis(diphenylphosphine)ferrocene]palladium dichloride (45 mg, 0.062 mmol), and potassium phosphate (328 mg, 1.55 mmol) were dissolved in 1,4-dioxane / water (10 mL / 1 mL), and the mixture was reacted overnight at 90 °C under nitrogen protection. The reaction solution was concentrated, and the residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate = 40 / 60) to give the racemic compound (162 mg, white solid), yield: 56%.

[0218] The racemic compound (100 mg) was prepared by chiral separation (chiral separation condition 2) to obtain compound 2-01 (43.5 mg, white solid) and compound 2-02 (46.8 mg, white solid). The absolute configuration was not determined.

[0219] Example compound 2-01 (corresponding to compounds with shorter retention times): MS (ESI): m / z 463.1 [M+H] + . 1H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.29 (s, 2H), 7.50-7.28 (m,7H), 4.36 (dd, J = 12.0, 4.8 Hz, 1H), 3.80 (s, 3H), 3.17-3.06 (m, 1H), 2.85-2.75 (m, 1H), 2.62-2.55 (m, 1H), 2.41-2.29 (m, 1H), 2.10-2.02 (m, 1H), 0.98-0.85 (m, 2H), 0.60-0.44 (m, 2H).

[0220] Example compound 2-02 (corresponding to compounds with longer retention times): MS (ESI): m / z 463.1 [M+H] + . 1 H NMR (400 MHz, DMSO-d6) δ 10.93 (s, 1H), 8.29 (s, 2H), 7.50-7.27 (m,7H), 4.36 (dd, J = 12.0, 4.8 Hz, 1H), 3.80 (s, 3H), 3.16-3.06 (m, 1H), 2.86-2.75 (m, 1H), 2.62-2.55 (m, 1H), 2.41-2.29 (m, 1H), 2.10-2.01 (m, 1H), 0.98-0.85 (m, 2H), 0.60-0.44 (m, 2H).

[0221] The compounds in the examples shown in Table 1 below were synthesized using the methods described in Examples 1 and 2. They were obtained by coupling reaction of the corresponding intermediate raw materials with intermediate 3 to obtain the corresponding racemic compounds. Then, the corresponding single chiral isomers were obtained by resolution using chiral separation condition one or chiral separation condition two.

[0222] Table 1

[0223]

[0224]

[0225] Test Example 1: VAV1 Degradation Activity

[0226] The degradation activity of the compounds on VAV1 was detected in the constructed Jurkat-VAV1-HiBiT-Knock in Cells. 40 μL of cells per well were seeded into 384-well plates in RPMI 1640, 10% FBS, and 1% Penicilin / Streptomycin. Different concentration gradients of the compounds were added to the cells, and the cells were cultured at 37°C and 5% CO2 for 24 h. The cell culture plates were equilibrated at room temperature for 10 min. In new EP tubes, LgBiT protein and Nano-Glo® HiBiT lysing substrate were diluted 1:100 and 1:50, respectively, to appropriate volumes of Nano-Glo® HiBiT lysing buffer and mixed thoroughly by inversion. 20 μL of Nano-Glo HiBiT lysing reagent was added to the plate, and the plate was shaken at 300 rpm for 3 min in the dark. The cell culture plates were incubated at 25°C for 15 min. Fluorescence parameters were read using a microplate reader.

[0227] The compound DC was fitted based on a nonlinear regression equation. 50 :Y=Bottom + (Top-Bottom) / (1+10^((LogDC 50 -X)*HillSlope)), X: compound concentration; Y: Degradation %; Top and Bottom: Plateaus in same units as Y; logDC 50 : same log units as X; HillSlope: Slope factor or Hill slope.

[0228] The results of compound detection are shown in Table 2, where A represents <1 nM, B represents 1-10 nM, C represents 10-100 nM, and D represents >100 nM.

[0229] The positive control drug MRT-6160 was prepared according to the method of compound 185 in Example 24 of WO2024 / 151547.

[0230] Table 2

[0231]

Claims

1. A compound of formula (I-1) or formula (I-2): Or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts, wherein: R 2 R 2 Each is independently selected from H, halogen, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl; R 3 Selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl. R 4 R 5 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl. Y 1 For N or CR c ; m is an integer between 0 and 3; R 6 Each is independently selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-6 membered cycloalkyl or optionally substituted 3-6 membered heterocycloalkyl. R c Each is selected from H, halogen, hydroxyl, cyano, amino, nitro, optionally substituted C1-C6 alkyl, optionally substituted C1-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl. R f Selected from optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C1-C6 alkoxy, optionally substituted 3-8 membered cycloalkyl, optionally substituted 3-8 membered heterocycloalkyl containing 1 to 2 heteroatoms selected from N, O, and S. R g Selected from arbitrarily substituted 5-10 membered heterocyclic groups containing 1 to 3 heteroatoms selected from N, O, and S.

2. The compound according to claim 1, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: R 3 Selected from H, halogen, hydroxyl, cyano, C1-C3 alkyl, C1-C3 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl, wherein the C1-C3 alkyl, C1-C3 alkoxy, 3-6 membered cycloalkyl or 3-6 membered heterocycloalkyl are optionally substituted with 1-3 halogens, C1-C3 alkyl, halogenated C1-C3 alkyl, C1-C3 alkoxy or halogenated C1-C3 alkoxy; R 3 H, F, Cl, Br, methyl, methoxy, trifluoromethyl, trifluoromethoxy, difluoromethyl, difluoromethoxy, cyclopropyl are preferred, and Cl is even more preferred.

3. The compound according to claim 1, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: R 4 R 5 Each is independently selected from H, F, methyl, trifluoromethyl, methoxy, or trifluoromethoxy, with H being preferred.

4. The compound according to claim 1, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: Y 1 For CR c ; R c The components are selected from H, F, Cl, methyl, methoxy, trifluoromethyl, and trifluoromethoxy, with H being preferred.

5. The compound according to claim 1, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: m can be 0, 1, or 2, with 0 being preferred; R 6 It is selected from H, halogen, hydroxyl, cyano, amino, nitro, methyl, trifluoromethyl, methoxy or trifluoromethoxy, with H being preferred.

6. The compound according to claim 1, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: R 2 R 2 Each is independently selected from H, F, Cl, C1-C3 alkyl groups optionally substituted with 1-3 halogens, C1-C3 alkoxy groups optionally substituted with 1-3 halogens, 3-6 membered cycloalkyl groups or 3-6 membered heterocycloalkyl groups optionally substituted with 1-3 halogens or C1-C3 alkyl groups, preferably H, F, Cl, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, difluoromethoxy, cyclopropyl.

7. The compound according to claim 1, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that: R f It is selected from C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, 3-8 membered cycloalkyl, 3-8 membered heterocycloalkyl, (C1-C3 alkylene)-(3-8 membered cycloalkyl), (C1-C3 alkylene)-(3-8 membered heterocycloalkyl), optionally substituted with 1-3 halogens, C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, C1-C3 alkylene, halo-C1-C3 alkyl, halo-C1-C3 alkylene, C1-C3 alkoxy, halo-C1-C3 alkoxy; R f Preferred compounds include C1-C3 alkyl, C2-C3 alkenyl, C2-C3 alkynyl, cyclopropyl, cyclobutyl, cyclopentyl, methylenecyclopropyl, methylenecyclobutyl, and methylenecyclopentyl. , , , , , , , , , Optionally substituted with 1-3 Cl, F, methyl, ethyl, =CH2, difluoromethyl, trifluoromethyl, =CF2, vinyl, ethynyl, -CH=CH2, methoxy, difluoromethoxy, or trifluoromethoxy; R f More , , , , , , , , , , , , , , , , , , , , , , , , , , , , .

8. The compound according to claim 1, or its deuterated derivatives, stereoisomers, or pharmaceutically acceptable salts thereof, characterized in that: R g Selected from 5-6 membered heterocyclic aryl groups containing 1-3 heteroatoms selected from N, O, and S, optionally substituted, and optionally substituted with 1-3 R atoms. h replace; R g Selected from , , , , , , , , , , , , , , , , , , Preferred , , , , , , , , , , , , ... , , Choose 1-3 Rs h replace; The R h The compounds are selected from halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered cycloalkyloxy groups, and (C1-C3 alkylene)-(3-6 membered cycloalkyl groups), wherein the C1-C3 alkyl groups, C1-C3 alkoxy groups, 3-6 membered cycloalkyl groups, 3-6 membered cycloalkyloxy groups, (C1-C3 alkylene)-(3-6 membered cycloalkyl groups), and C1-C3 alkylene groups are optionally substituted with 1-3 halogens, C1-C3 alkyl groups, C1-C3 alkoxy groups, halo-C1-C3 alkyl groups, and halo-C1-C3 alkoxy groups; The R h Preferably, Cl, F, methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, cyclopropyloxy, cyclobutyl, and methylenecyclobutyl are used, wherein the methyl, ethyl, propyl, cyclopropyl, methylenecyclopropyl, methoxy, cyclopropyloxy, cyclobutyl, and methylenecyclobutyl are optionally substituted by 1-3 Cl, F, methyl, trifluoromethyl, difluoromethyl, methoxy, trifluoromethoxy, and difluoromethoxy groups. The R h More preferably Cl, F, methyl, propyl, difluoromethyl, trifluoromethyl, Cyclopropyl, methylenecyclopropyl, , , Methoxy, Difluoromethoxy, Trifluoromethoxy, ... , , , Cyclobutyl , .

9. The compound according to claim 1, or its deuterated derivative, stereoisomer, or pharmaceutically acceptable salt thereof, characterized in that, Selected from the following compounds: 。 10. A pharmaceutical composition for degrading VAV1 protein, comprising the compound according to any one of claims 1-9, its deuterated form, stereoisomer, or pharmaceutically acceptable salt, and its pharmaceutically acceptable carrier.

11. The pharmaceutical composition according to claim 10, characterized in that, The pharmaceutical composition mediates the interaction between VAV1 protein and E3 ligase, thereby increasing the degradation of VAV1 protein.

12. Use of the compound, its deuterated form, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or 11, in the preparation of a medicament for treating and / or preventing diseases caused by or related to VAV1 polymorphism.

13. The use of the compound, its deuterated form, stereoisomer, or pharmaceutically acceptable salt according to any one of claims 1-9, or the pharmaceutical composition according to claim 10 or 11, in the preparation of a medicament for treating and / or preventing diseases caused by or related to immune abnormalities.

14. The use according to claim 12 or 13, characterized in that, The diseases referred to are autoimmune diseases, inflammatory diseases, allergic diseases, and tumors.

15. The use according to claim 14, characterized in that, The autoimmune diseases mentioned are selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, Hashimoto's thyroiditis, myasthenia gravis, Sjögren's syndrome, Graves' disease, type I diabetes and related diseases, vasculitis, urticaria, pulmonary hypertension, pemphigus, pernicious anemia and blood diseases mediated by autoimmune abnormalities, uveitis, psoriasis, Graves' ophthalmopathy, alopecia areata and other diseases, autoimmune nephritis, cutaneous manifestations of immune-mediated diseases, systemic sclerosis, morphine scleroderma, graft-versus-host disease, T-cell mediated nephropathy, biliary sclerosis, sclerosing cholangitis, autoimmune liver disease, chronic inflammatory demyelinating diseases, ankylosing spondylitis, axial spondyloarthritis, and alopecia areata. The inflammatory diseases mentioned include asthma, inflammatory lung injury, inflammatory liver injury, inflammatory glomerular injury, atherosclerosis, osteoarthritis, irritant contact dermatitis and eczematous dermatitis, seborrheic dermatitis, inflammatory eye disease, keratoconjunctivitis, pericarditis, myocarditis, hepatitis, pulmonary fibrosis, macular degeneration, generalized varicella-zoster, Alzheimer's disease, and amyloidosis; The allergic diseases mentioned include allergic asthma, atopic dermatitis, allergic rhinitis / conjunctivitis, allergic contact dermatitis, and esophagitis.

16. The use according to claim 15, characterized in that, The diseases mentioned are selected from inflammatory bowel disease, rheumatoid arthritis, multiple sclerosis, lupus erythematosus, psoriasis, type I diabetes, myasthenia gravis, chronic inflammatory demyelinating diseases, graft-versus-host disease, ankylosing spondylitis, and axial spondyloarthritis.

17. The use according to claim 16, characterized in that, The diseases mentioned are selected from ulcerative colitis, Crohn's disease, rheumatoid arthritis, multiple sclerosis, systemic lupus erythematosus, psoriasis, type I diabetes, myasthenia gravis, and graft-versus-host disease.

18. The use according to claim 17, characterized in that, The diseases mentioned are selected from ulcerative colitis, rheumatoid arthritis, and multiple sclerosis.

19. The use according to claim 14, characterized in that, The tumors include solid tumors and hematologic malignancies, especially hematologic malignancies; the hematologic malignancies include T-cell and B-cell malignancies.

20. The use according to claim 19, characterized in that, The malignant tumors of the hematologic system are selected from: leukemia and lymphoma.

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